Stroke is a debilitating disease which affects more than 400,000 persons per year in the United States alone. At current trends, this number is projected to jump to one million per year by the year 2050. When the direct costs (care and treatment) and the indirect costs (lost productivity) of strokes are considered together, strokes put a burden of $43.3 billion per year on the society of the United States alone. In 1990 cerebrovascular diseases were the second leading cause of death worldwide, killing over 4.3 million people world wide. Stroke is characterized by the sudden loss of circulation to an area of the brain, resulting in a corresponding loss of neurologic function. Also called cerebrovascular accident or stroke syndrome, stroke is a nonspecific term encompassing a heterogeneous group of pathophysiologic causes, including thrombosis, embolism, and hemorrhage. Strokes currently are classified as either hemorrhagic or ischemic. Acute ischemic stroke refers to strokes caused by thrombosis or embolism and account for 80% of all strokes.
Ischemic strokes result from blockage of the arteries that supply the brain, most commonly in the branches of the internal carotid arteries. The blockage usually results when a piece of a blood clot (thrombus) or of a fatty deposit (atheroma) due to atherosclerosis breaks off (becoming an embolus), travels through the bloodstream, and lodges in an artery that supplies the brain. Blood clots may form when a fatty deposit in the wall of an artery ruptures. The rupture of such a fatty deposit may also form when a large fatty deposit slows blood flow, reducing it to a trickle. Blood that flows slowly is more likely to clot. Thus, the risk of a clot forming in and blocking a narrowed artery is high. Blood clots may also form in other areas, such as in the heart or on a heart valve. Strokes due to such blood clots are most common among people who have recently had heart surgery and people who have a heart valve disorder or an abnormal heart rhythm (arrhythmia), especially atrial fibrillation. Also, in certain disorders such as an excess of red blood cells (polycythemia), the risk of blood clots is increased because the blood is thickened.
An ischemic stroke can also result, if the blood flow to the brain is reduced, as may occur when a person loses a lot of blood or has very low blood pressure. Occasionally, an ischemic stroke occurs when blood flow to the brain is normal but the blood does not contain enough oxygen. Disorders that reduce the oxygen content of blood include severe anemia (a deficiency of red blood cells), suffocation, and carbon monoxide poisoning. Usually, brain damage in such cases is widespread (diffuse), and coma results. An ischemic stroke can occur, if inflammation or infection narrows blood vessels that supply the brain. Similarly, drugs such as cocaine and amphetamines can cause spasm of the arteries, which can lead to a narrowing of the arteries supplying the brain to such an extent that a stroke is caused.
Most ischemic strokes begin suddenly, develop rapidly, and cause death of brain tissue within minutes to hours. Then most strokes become stable, causing little or no further damage. (Strokes that remain stable for 2 to 3 days are called completed strokes.) Such strokes are more likely to be due to sudden blockage by an embolus. Less commonly, strokes may continue to worsen for several hours to a day or two, as a steadily enlarging area of brain tissue dies. (Such strokes are called evolving strokes.) The progression is usually interrupted by somewhat stable periods, during which the area temporarily stops enlarging or some improvement occurs. Such strokes are more likely to be due to formation of clots in a narrowed artery.
Many different symptoms can occur, depending on which part of the brain is deprived of blood and oxygen. When the arteries that branch from the internal carotid artery are affected, blindness in one eye or abnormal sensations and weakness in one arm or leg or on one side of the body are most common. When the arteries that branch from the vertebral arteries in the back of the brain are affected, dizziness and vertigo, double vision, and generalized weakness of both sides of the body are more common. Many other symptoms, such as difficulty speaking (for example, slurred speech) and loss of coordination, can occur. Large strokes may lead to stupor or coma. In addition, strokes, even small ones, can cause depression or an inability to control emotions (causing inappropriate crying or laughing). Strokes can cause swelling in the brain due to accumulation of fluid (edema). Swelling in the brain is particularly dangerous because the skull does not expand. The resulting increase in pressure can cause the brain to shift and damage brain tissue further, making neurologic dysfunction worse, even if the area affected by the stroke itself does not enlarge. If the pressure becomes very high, the brain may even be forced downward in the skull, resulting in herniation of the brain.
In the past, almost nothing could be done to help patients with acute stroke. Recently advances have been made in stroke prevention, supportive care, and rehabilitation. For an evolving stroke, anticoagulants such as heparin may be given, but their effectiveness has not been proved. After the stroke is completed, anticoagulants are given to prevent subsequent strokes in people who have atrial fibrillation or a heart valve disorder. However, because these drugs increase the risk of bleeding into the brain, doctors usually wait at least 24 hours after thrombolytic therapy is ended before anticoagulants are started. Anticoagulants are not given to people who have uncontrolled high blood pressure or who have had a hemorrhagic stroke. Accordingly, there is still a large need in the art to develop novel therapeutic compounds capable of preventing, treating or ameliorating the severe health consequences of stroke including death.